MicroRNA regulation of the proliferation and apoptosis of Leydig cells in diabetes

Molecular Medicine

Shaochai Wei¹  Xiangwei Wang²  Yuqi Wu²  Pei Zhu²  Shulin Li²  Li Hu³ 

[1] Department of Physiology, Shantou University of Medical College, 515041, Shantou, People’s Republic of China;Department of Urology & Carson International Cancer Center, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy Center, Shenzhen University, NO.1098, Xueyuan Road, Shenzhen University City, Nanshan District, 518055, Shenzhen, People’s Republic of China;Shenzhen University South China Hospital, Shenzhen University, 518111, Shenzhen, People’s Republic of China;Department of Physiology, Shantou University of Medical College, 515041, Shantou, People’s Republic of China;

关键词: Testicular damage;    Diabetes mellitus;    Testosterone;    Small RNA;    MAPK signalling pathway;   

DOI  :  10.1186/s10020-021-00370-8

来源: Springer

【 摘 要 】

BackgroundThe number of patients with diabetes is increasing worldwide. Diabetic testicular damage can cause spermiogenesis disorders and sexual dysfunction. We thus explored the role of miRNAs in diabetic testicular damage, and revealed that they could serve as effective prevention and treatment therapeutic targets.MethodsStreptozotocin (STZ) was used to generate a rat model of type 2 diabetes. Rat testicular tissues were used for miRNA and mRNA sequencing. Through bioinformatics analysis, we constructed an miRNA–mRNA diabetic testicular damage regulatory network and screened for key miRNAs. We also used Leydig cells to generate a diabetic cell model and detected the downstream target genes of miRNAs, secretion of testosterone, and proliferation and apoptotic levels to elucidate the role and mechanism of the selected miRNAs in diabetic testicular damage.ResultsUsing second-generation sequencing, we identified 19 differentially expressed miRNAs and 555 mRNAs in the testes of diabetic rats. Based on computational prediction of targets and negative regulation relationships, we constructed a miRNA–mRNA regulatory network, including 12 miRNAs and 215 mRNAs. KEGG enrichment analysis revealed that genes were more concentrated on the survival signalling pathway. Based on this, we screened 2 key miRNAs, miR-504 and miR-935. In vitro, glucose could induce an increase in miR-504 and miR-935, whereas a decrease in MEK5 and MEF2C in a dose-dependent manner. Overexpression of miR-504 and miR-935 led to the decreased expression of MEK5 and MEF2C, decreased proliferation rate of Leydig cells, increased apoptotic rate, and decreased secretion of testosterone. Whereas, knockdown of miR-504 and miR-935 displayed opposite tendencies.ConclusionsmiRNAs play important roles in diabetic testicular damage. miR-504 and miR-935 might regulate testicular damage through the classic survival pathway of MEK5-ERK5-MEF2C. Targeted inhibition of miR-504 and miR-935 could reverse the high-glucose-induced testicular complications, thus posing as a potential therapeutic approach in diabetic testicular injury.

【 授权许可】

CC BY